氟氢可的松 | 127-31-1

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 肾上腺皮质激素类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 氟氢可的松
• 英文名称: Fludrocortisone
• 英文别名: (8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
• CAS: 127-31-1
• 化学式: C₂₁H₂₉FO₅
• mdl: MFCD00083333
• 分子量: 380.457
• InChiKey: AAXVEMMRQDVLJB-BULBTXNYSA-N

物化性质

• 熔点：
  208-212°C
• 比旋光度：
  D23 +139° (c = 0.55 in 95% ethanol)
• 沸点：
  564.7±50.0 °C(Predicted)
• 密度：
  1.1176 (estimate)
• 溶解度：
  可溶于DMSO（轻微）、乙醇（轻微、加热）、甲醇（轻微、超声处理）
• 物理描述：
  Solid
• 颜色/状态：
  Crystals
• 蒸汽压力：
  1.65X10-13 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Fludrocortisone acetate tablets should be stored in well-closed containers at room temperature; excessive heat should be avoided. /Fludrocortisone acetate/
• 旋光度：
  Specific optical rotation: 139 deg at 23 °C/D (c= 0.55 in 95% ethanol)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.809
• 拓扑面积：
  94.8
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

关于氟氢可的松在体内的具体代谢途径信息非常有限。氟氢可的松的9α-氟化似乎极大地简化了其代谢过程，与其他皮质类固醇相比——虽然已经观察到通过11-羟基类固醇脱氢酶的氧化反应，但这种反应受到很大程度的阻碍，因为氟原子基团似乎赋予了对抗这些酶的11β-氧化的“保护”。11β-氧化减少被认为是氟氢可的松具有显著盐皮质激素效力背后的原因之一。在体外研究中，仅在人类肝微粒体和细胞质中孵化后产生了两种代谢物，分别为20β-二氢氟氢可的松和6β-羟基氟氢可的松，并且没有详细探索可能负责这种反应的潜在酶。鉴于氟氢可的松是一种皮质类固醇，这类药物已知由CYP3A家族代谢，并且不建议与强效的CYP3A抑制剂/诱导剂联合使用，CYP3A家族的酶可能在某种程度上参与了其代谢（尽管这一信息似乎并没有特别针对氟氢可的松进行阐明）。

There exists is a paucity of information regarding the specific metabolic pathway _in vivo_ of fludrocortisone. The 9α-fluorination of fludrocortisone appears to greatly simplify its metabolism as compared to other corticosteroids - while oxidation via 11-hydroxysteroid dehydrogenases has been observed, this reaction is greatly impaired as the fluorine moiety appears to confer "protection" from 11β-oxidation by these enzymes. The reduction in 11β-oxidation is thought to be one of the reasons behind fludrocortisone's profound mineralocorticoid potency. An _in vitro_ study generated only two metabolites following incubation in human liver microsomes and cytosol, namely 20β-dihydrofluorocortisol and 6β-hydroxyfluorocortisol, and did not explore in detail the potential enzymes responsible for this reaction. Given that fludrocortisone is a corticosteroid, a class of medications known to be metabolized by the CYP3A family, and is not recommended to be given with strong inhibitors/inducers of CYP3A, it is likely that the CYP3A family of enzymes contributes in some way to its metabolism (though this information does not appear to have been specifically elucidated for fludrocortisone).

来源:DrugBank

代谢

研究的是肾脏切片、匀浆和孤立灌流的肾脏。主要代谢物是20(ε)-二氢-9α-氟可的松。只有9α-氟可的松，没有代谢物，与细胞溶质受体结合。

STUDIED WERE KIDNEY SLICES, HOMOGENATES, & ISOLATED PERFUSED KIDNEYS. MAJOR METABOLITE: 20(EPSILON)-DIHYDRO-9ALPHA-FLUOROCORTISOL. ONLY 9ALPHA-FLUOROCORTISOL, NO METABOLITES, BOUND TO CYTOSOLIC RECEPTORS.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

化合物：氟氢可的松

Compound:fludrocortisone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 相互作用

同时使用含钠食物或药物与氟氢可的松治疗IV型肾小管酸中毒可能会导致高钠血症、水肿，以及血压的潜在严重升高；可能需要调整钠的摄入量。

Concurrent use /of sodium-containing foods or medications/ with fludrocortisone in the treatment of Type IV renal tubular acidosis may result in hypernatremia, edema, and potentially severe increases in blood pressure;adjustment of sodium intake may be required.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

口服给药后，氟氢可的松的吸收迅速且完全。药代动力学研究估计其Cmax为0.0012至0.20 μg/L，Tmax在0.5至2小时之间。口服给药后，氟氢可的松的AUC0-∞估计值在不同研究中有所不同，介于1.22至3.07 μg·h/L之间。

Absorption of fludrocortisone following oral administration is rapid and complete. Pharmacokinetic studies have estimated the Cmax to be 0.0012 to 0.20 μg/L with a Tmax between 0.5 and 2 hours. The AUC0-∞ of fludrocortisone after oral administration has been variably estimated to be between 1.22 to 3.07 μg.h/L.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约80%的服用的氟氢可的松剂量会出现在尿液中，其余20%可能通过粪便或胆道途径排出。

Approximately 80% of an administered dose of fludrocortisone shows up in the urine, with the other 20% likely eliminated via fecal or biliary route.

来源:DrugBank

吸收、分配和排泄

• 分布容积

醋酸氟氢可的松的表观分布容积为80-85升。进入脑脊液的分布似乎很少 - 观察到的脑脊液药物浓度与血浆药物浓度的比率为1:6。

The apparent volume of distribution of fludrocortisone is 80-85 L. Distribution into CSF appears minimal - the observed ratio of CSF drug concentration versus plasma drug concentration is 1:6.

来源:DrugBank

吸收、分配和排泄

• 清除

群体药代动力学估计氟氢可的松的血浆清除率为40.8升/小时。

Population pharmacokinetics have estimated the plasma clearance of fludrocortisone to be 40.8 L/h.

来源:DrugBank

吸收、分配和排泄

消除：主要通过肾脏，以无活性代谢物的形式。

Elimination: Renal, mostly as inactive metabolites.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S22,S26,S36
• 危险类别码：
  R63
• 海关编码：
  2937210000
• 储存条件：
  | 冰箱 |

制备方法与用途

生物活性：Fludrocortisone 是一种合成的盐皮质激素，具备显著的抗炎作用。

反应信息

• 作为反应物：
  描述：

  氟氢可的松 生成 (8S,9R,10S,11S,13S,14S,16R,17S)-9-氟-11,16,17-三羟基-17-(2-羟基乙酰基)-10,13-二甲基-1,2,6,7,8,11,12,14,15,16-十氢环戊烯并[a]菲-3-酮
  参考文献：
  名称：

  Oxidation of Steroids by Microorganisms. IV. 16α-Hydroxylation of 9α-Fluorohydrocortisone and 9α-Fluoroprednisolone by Streptomyces roseochromogenus

  摘要：

  DOI：

  10.1021/ja01574a070
• 作为产物：
  描述：

  醋酸氟氢可的松 在 potassium carbonate 作用下， 生成 氟氢可的松
  参考文献：
  名称：

  Halogenated Corticoids. I. 9α-Halogen Derivatives of Cortisone and Hydrocortisone^*

  摘要：

  DOI：

  10.1021/ja01562a030

文献信息

• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。
• [EN] COMPOUNDS AS MODULATORS OF TIGIT SIGNALLING PATHWAY<br/>[FR] COMPOSÉS MODULATEURS DE LA VOIE DE SIGNALISATION DE TIGIT
  申请人：AURIGENE DISCOVERY TECH LTD

  公开号：WO2018047139A1

  公开（公告）日：2018-03-15

  The present invention relates to compound of formula (I) as therapeutic agents to modulate the TIGIT signalling pathway. The invention also encompasses the use of the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by TIGIT.

  本发明涉及一种化合物，其化学式为（I），作为调节TIGIT信号通路的治疗剂。该发明还涵盖了利用化合物（I）或其立体异构体或其药学上可接受的盐来治疗由TIGIT介导的疾病或紊乱。
• PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY
  申请人：Rewcastle Gordon William

  公开号：US20110009405A1

  公开（公告）日：2011-01-13

  Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

  本文提供了式I的嘧啶基和1,3,5-三嗪基苯并咪唑化合物，以及它们的药物组合物、制备方法，以及作为抗癌治疗药物或药剂的用途，可以单独使用，也可以与放疗和/或其他抗癌药物联合使用。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。